PXRD INVESTIGATION OF CHANGES IN DEHYDRATION BEHAVIOR OF GSK HYDRATE AFTER MICRONIZATION

Transcription

1 PXRD INVESTIGATION OF CHANGES IN DEHYDRATION BEHAVIOR OF GSK HYDRATE AFTER MICRONIZATION Feirong Kang Physical Properties Group - Pharmaceutical Development GlaxoSmithKline King of Prussia, PA

2 This document was presented at PPXRD - Pharmaceutical Powder X-ray Diffraction Symposium Sponsored by The International Centre for Diffraction Data This presentation is provided by the International Centre for Diffraction Data in cooperation with the authors and presenters of the PPXRD symposia for the express purpose of educating the scientific community. All copyrights for the presentation are retained by the original authors. The ICDD has received permission from the authors to post this material on our website and make the material available for viewing. Usage is restricted for the purposes of education and scientific research. PPXRD Website ICDD Website -

3 Outlines Background and Objectives Methodologies on Dehydration Analysis Thermal analysis DSC/TGA Hot-stage microscopy Gravimetric vapour Sorption Isothermal dehydration Kinetics modelling PXRD analysis Reflection vs. transmission Variable temperature PXRD Rieveltd refinement Conclusions

4 Background Many pharmaceuticals exist in both hydrated and anhydrous forms. The physicochemical, mechanical, processing, and biological properties of hydrates may differ significantly from those of the corresponding anhydrates. Understanding of dehydration behavior is required for process control and predicting stability of drug substance and drug product. Variable hydrates present relative complex dehydration behavior compared to stochiometrirc hydrates.

5 Compound in Study Form B, a hydrated form of this free base was chosen for development. Theoretical monohydrate 4.6%wt Classified as a variable, or non- stoichiometric hydrate Displays complex dehydration behavior pre and post size reduction 7-methoxy-1-methyl-5-(4- (trifluoromethyl)phenyl)- [1,2,4]triazolo[4,3-a]quinolin-4- amine (GSK241572)

6 Objectives Characterize dehydration of the system pre- and post-micronization Various techniques were utilized including DSC, TGA, HSM, GVS, VT-PXRD etc. Study dehydration mechanism by the following approaches Solid state kinetics modeling Rietveld analysis Crystal structural analysis

7 Scanning Electron Microscopy Pre-micronization 100X Pre-micronization 2000X Post-micronization 100X Post-micronization 77566X

8 DSC/TGA Pre-micronization Post-micronization 2 Melt Melt Heat Flow (W/g) -2-4 Dehydration 3.803% (0.7953mg) Weight (%) Heat Flow (W/g) -4-6 Dehydration 2.659% (0.1450mg) Weight (%) -6 Dehydration /form conversion Exo Up Temperature ( C) Universal V4.2E TA Instruments Exo Up Temperature ( C) Universal V4.2E TA Instruments Distinct dehydration processes observed between non-micronized and micronized samples.

9 Hot-Stage Microscopy Pre-micronization Post-micronization Initial Initial Start recrystallization to needle-like crystals (anhydrous form) 160 C Bubbles 150 C Start recrystallization to needle-like crystals (anhydrous form) 200 C 200 C Converted to anhydrous form Converted to anhydrous form

10 Isothermal Dehydration NETZSCH Thermokinetics isothermal dehydration Mass/% 99.5 Non-micronized Micronized Equilibrated at 40% RH, upon a step to 0% RH, the dehydration was monitored at 25 ºC Time/min Drastically different behavior displayed with regards to the loss of water content over time. The rate of loss of non-micronized material is slower by ~ two orders of magnitude.

11 GVS Isotherms exchange of lattice (channel) water primarily surface sorption/desorption GVS isotherms (25 C) for the interaction of water with micronized and non-micronized FormB.

12 Kinetic Modeling Non-micronized NETZSCH Thermokinetics unmic dehydration by GVS Mass/% Step 1: 2-dim. diffusion Step 2: 2nd order 60.0 C 40.0 C 25.0 C Corr. coeff Log A 1 (1/s) 155 E 1 (kj/mol) 910 Log A 2 (1/s) 1.7 E 2 (kj/mol) Time/min

13 Kinetic Modeling Micronized NETZSCH Thermokinetics mic dehydration by GVS Mass/% nd order 60.0 C 40.0 C 25.0 C 98.5 Corr. coeff Log A 1 (1/s) E 1 (kj/mol) Time/min

14 Summary so far. DSC, TGA, HSM, and GVS data showed distinct dehydration process between non-micronized and micronized materials. Kinetics modeling on dehydration showed The non-micronized material exhibits a two-step dehydration process where a diffusion step is followed by a 2 nd order step. The diffusion step is the rate limiting step based on that its dehydration activation energy is ~22 times higher than the 2 nd step. The micronized material follows a simple one-step process (2 nd order) PXRD analysis will be discussed next to rationalize results.

15 Crystallographic Data Moiety formula Crystal system Temperature Space group C 19 H 15 F 3 N 4 O H 2 O Triclinic 150(2) K Unit cell dimensions a = 8.473(6) Å α= (4) Volume (18) Å 3 Z 4 P 1 b = (7) Å β= (5) c = (9) Å γ = 94.86(8) Density (calculated) Mg/m 3

16 PXRD Intensity (counts) Transmission mode Non-micronized 5000 Micronized Single crystal prediction Theta ( ) Line intensity change is due to preferred orientation No baseline increase and peak broadening no phase separated amorphous content or significant degradation of crystallite integrity

17 Reflection Analysis Non-Micronized Counts x4284i1 x4284i % Position [ 2Theta]

18 Reflection Analysis Non-Micronized View down a-axis (204) (02-1) (011) (003) (002) Water channels

19 Reflection Analysis Micronized Counts x4284i1 x4284i % Position [ 2Theta]

20 Transmission Analysis Non-Micronized Counts x4284i1 x4284i % Position [ 2Theta]

21 Reflection Transmission b a Water channels along a-axis c Schematic drawing showing orientation of a non-micronized particle in x-ray sample holder

22 VT-PXRD Non-Micronized Intensity (counts ) C C 100 C C 70 C C Ambient Theta ( ) Form change observed at 150 C Line shifting (up to 100 C) less than 0.1 2θ

23 VT-PXRD Micronized Intensity (counts ) C C 100 C C 70 C 50 C Ambient Theta ( ) Form change observed at 150 C

24 VT-PXRD Micronized Intensity (counts) C 90 C (011) (002) Zoom in θ θ θ (0-21) C C 1000 Ambient θ θ θ Theta ( ) Line shifting θ to both lower and higher d-spacing directions changes to the unit cell are anisotropic between the hydrated and dehydrated states

25 Crystal Lattice Change upon Thermal Dehydration Rietveld Analysis (HighScore Plus) a / Å b / Å c / Å α / β / γ / V / Å 3 V %change mic INT % mic 50C % mic 70C % mic 90C % mic 100C % non-mic INT % non-mic 50C % non-mic 70C % non-mic 90C % non-mic 100C %

26 Change in Cell Volume upon Thermal Dehydration 2.5% Change in cell vo olume (%) 2.0% 1.5% 1.0% 0.5% 0.0% -0.5% -1.0% Cell Volume (mic) Cell Volume (non-mic) thermal expansion > water loss contraction thermal expansion < water loss contraction Temp (degree C)

27 Slip Planes A A. (0 0 1) face (E att = kcal/mol), showing lack of egress channels for water B. (0 1 0) face (E att = kcal/mol), C. (1 0-1) face (E att = kcal/mol), both showing egress channels for water B C Calculated using the COMPASS forcefield

28 Conclusions The drastic change in dehydration behavior of the hydrate after micronization is mainly due to Breakage of water channels through longest dimension (a-axis) shorten water travel length Cleavage of several crystal faces that have low attachment energy create more channels for water to escape PXRD analyses provide insight into the change of dehydration behavior.

29 Acknowledgements Glenn Williams Fred Vogt Rachel Forcino Jeff Brum Roy Copley